Sarcoidosis is a multisystem granulomatous disease of unknown etiology that has worldwide prevalence. In the United States, it most commonly affects African Americans who are less than 40 years of age. The pathologic, epidemiologic, and immunologic features of sarcoidosis are similar to Mycobacterium infections, particularly tuberculosis. In preliminary studies, polymerase chain reaction (PCR) analysis revealed sequences corresponding to Mycobacterium species in 15 of 25 paraffin-embedded granulomas from sarcoidosis patients local to Nashville, TN, but none of 25 control specimens from the same locale (p<0.00002, chi square). This analysis was expanded to include frozen specimens from other regions of the United States, in which mycobacterial nucleic acid was amplified from 50% of frozen sarcoidosis specimens and none of control tissues (p<0.016, Fisher's exact test). These findings lead to the hypothesis that sarcoidosis is an immunologic response in a genetically susceptible host to mycobacterial infection, involving a novel Mycobacterium which is closely related to Mycobacterium tuberculosis. The proposed research will test this hypothesis by (i) evaluating sarcoidosis specimens for the presence of immunodominant genes associated with virulence in mycobacterial infections, and (ii) comparing antigen specific T-cell responses in sarcoidosis patients with normal healthy controls, and patients with M. tuberculosis infection. This work will contribute important new information about the etiology of sarcoidosis and establish a strong experimental framework for ongoing studies of the immunopathogenesis of this disease.